Glaucoma is a leading cause of blindness world-wide and the second leading cause of blindness in the United States. It is estimated that as many as 50% of affected individual do not realize that they have glaucoma. For many individuals, irreversible damage will have occurred by the time diagnosis and intervention have begun. Because treatments exist that can slow or stop progression of the disease, presymptomatic testing could potentially save sight in many individuals. Because the existing treatments do not work equally well for everyone, improved treatment approaches are also needed. Our long-range goal is to map and identify genes responsible for both open-angle and angle-closure forms of glaucoma, and to use cloned copies of the genes as tools with which to explore the underlying mechanisms of the disease, develop presymptomatic testing, and design novel approaches to therapy and prevention. The approach of this project is to identify the location glaucoma genes on human chromosomes and to do mutation screening of candidate genes located at the site of mapped glaucoma genes. A collection of more than 400 glaucoma families will form the core of the mapping project. Data from genome scans will be analyzed under dominant, recessive and model-free assumptions to identify locations of genes responsible for simple and genetically complex forms of glaucoma. Fine-scale mapping will be carried out in the immediate vicinity of the known glaucoma genes. Genes that have already been mapped to the region for which linkage was detected will be evaluated for the presence of mutations in affected family members. Successes during the previous funding period including cloning of one syndromic glaucoma gene, mapping of genes for two other disorders that include glaucoma, and mapping of several regions in which we find evidence for glaucoma genetic risk factors. Identification of new glaucoma genes will enhance our understanding of disease processes and assist in development of new diagnostic tests.